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Multicenter Study
. 2023 Jan;60(1):65-73.
doi: 10.1136/jmedgenet-2021-108006. Epub 2021 Dec 6.

Phenotypic spectrum and clinical course of single large-scale mitochondrial DNA deletion disease in the paediatric population: a multicentre study

Kristoffer Björkman  1   2 , John Vissing  3 , Elsebet Østergaard  4   5 , Laurence A Bindoff  6   7 , Irenaeus F M de Coo  8   9 , Martin Engvall  10   11 , Omar Hikmat  6   12 , Pirjo Isohanni  13   14 , Gittan Kollberg  15 , Christopher Lindberg  16 , Kari Majamaa  17   18 , Karin Naess  10   19 , Johanna Uusimaa  20   21 , Mar Tulinius  22   2 , Niklas Darin  22   2
Affiliations
Multicenter Study

Phenotypic spectrum and clinical course of single large-scale mitochondrial DNA deletion disease in the paediatric population: a multicentre study

Kristoffer Björkman et al. J Med Genet. 2023 Jan.

Abstract

Background: Large-scale mitochondrial DNA deletions (LMD) are a common genetic cause of mitochondrial disease and give rise to a wide range of clinical features. Lack of longitudinal data means the natural history remains unclear. This study was undertaken to describe the clinical spectrum in a large cohort of patients with paediatric disease onset.

Methods: A retrospective multicentre study was performed in patients with clinical onset <16 years of age, diagnosed and followed in seven European mitochondrial disease centres.

Results: A total of 80 patients were included. The average age at disease onset and at last examination was 10 and 31 years, respectively. The median time from disease onset to death was 11.5 years. Pearson syndrome was present in 21%, Kearns-Sayre syndrome spectrum disorder in 50% and progressive external ophthalmoplegia in 29% of patients. Haematological abnormalities were the hallmark of the disease in preschool children, while the most common presentations in older patients were ptosis and external ophthalmoplegia. Skeletal muscle involvement was found in 65% and exercise intolerance in 25% of the patients. Central nervous system involvement was frequent, with variable presence of ataxia (40%), cognitive involvement (36%) and stroke-like episodes (9%). Other common features were pigmentary retinopathy (46%), short stature (42%), hearing impairment (39%), cardiac disease (39%), diabetes mellitus (25%) and renal disease (19%).

Conclusion: Our study provides new insights into the phenotypic spectrum of childhood-onset, LMD-associated syndromes. We found a wider spectrum of more prevalent multisystem involvement compared with previous studies, most likely related to a longer time of follow-up.

Keywords: and neonatal diseases and abnormalities; congenital; hereditary; paediatrics; phenotype; prognosis; sequence deletion.

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Conflict of interest statement

Competing interests: KM has received support for attending meetings and travel from Nordic Infucare and Biogen Finland. IFMdC has received consulting fees from Reneo Pharma.

Figures

Figure 1
Figure 1
Onset age in years of major clinical features. Patients for which a precise feature onset date is not known are excluded. Within each box, the horizontal lines denote the median values; boxes extend from the 25th to the 75th percentile of each group’s distribution of values; vertical extending lines denote adjacent values (ie, the most extreme values within 1.5 IQR of the 25th and 75th percentile of each group); dots denote observations outside the range of adjacent values. PEO, progressive external ophthalmoplegia.
Figure 2
Figure 2
Kaplan-Meier analysis of survival since disease onset for patients of the KSS spectrum (n=40), PEO (n=23) and PS (n=17) groups. KSS, Kearns-Sayre syndrome; PEO, progressive external ophthalmoplegia; PS, Pearson syndrome.
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References

    1. Holt IJ, Harding AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 1988;331:717–9. 10.1038/331717a0 - DOI - PubMed
    1. Chinnery PF, DiMauro S, Shanske S, Schon EA, Zeviani M, Mariotti C, Carrara F, Lombes A, Laforet P, Ogier H, Jaksch M, Lochmüller H, Horvath R, Deschauer M, Thorburn DR, Bindoff LA, Poulton J, Taylor RW, Matthews JNS, Turnbull DM. Risk of developing a mitochondrial DNA deletion disorder. Lancet 2004;364:592–6. 10.1016/S0140-6736(04)16851-7 - DOI - PubMed
    1. Schaefer AM, McFarland R, Blakely EL, He L, Whittaker RG, Taylor RW, Chinnery PF, Turnbull DM. Prevalence of mitochondrial DNA disease in adults. Ann Neurol 2008;63:35–9. 10.1002/ana.21217 - DOI - PubMed
    1. Remes AM, Majamaa-Voltti K, Kärppä M, Moilanen JS, Uimonen S, Helander H, Rusanen H, Salmela PI, Sorri M, Hassinen IE, Majamaa K. Prevalence of large-scale mitochondrial DNA deletions in an adult Finnish population. Neurology 2005;64:976–81. 10.1212/01.WNL.0000154518.31302.ED - DOI - PubMed
    1. Darin N, Oldfors A, Moslemi AR, Holme E, Tulinius M. The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA abnormalities. Ann Neurol 2001;49:377–83. 10.1002/ana.75 - DOI - PubMed

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